Clinical Pearls & Morning Reports
Published September 23, 2020
Congenital adrenal hyperplasia (CAH) — one of the most common autosomal recessive disorders — is potentially life-threatening in its classic (severe) form and may be asymptomatic or cause female infertility in its nonclassic (mild) form. The most common type of CAH is 21-hydroxylase deficiency. Today, the classic form is the most common cause of atypical genitalia in 46,XX newborns and of primary adrenal insufficiency during childhood. Read the NEJM Review Article here.
Q: What is the basic pathology underlying most cases of CAH?
A: Mutations in CYP21A2 (the gene encoding 21-hydroxylase, a cytochrome P-450 enzyme) result in lack of 21-hydroxylase, which is required for the production of cortisol and aldosterone in the adrenal cortex. Reduced cortisol leads to overproduction of pituitary corticotropin, which stimulates the accumulation of cortisol precursors and their subsequent diversion through the steroid pathways that produce adrenal androgens. Unlike the therapeutic approaches to other forms of adrenal insufficiency, therapeutic goals in CAH are twofold: first, to replace deficient hormones, and second, to reduce excessive androgen levels.
Q: How do most protocols screen for CAH in newborns?
A: Most cases of CAH in infants are first detected by means of newborn screening, which has reduced morbidity and mortality and has led to less severe hyponatremia and shorter hospitalizations at diagnosis. Protocols for detection vary but are mostly based on the presence of elevated 17-hydroxyprogesterone levels on immunoassay. Despite the reduction in infant mortality as a result of neonatal screening for CAH, patients of all ages are at risk for death from adrenal crises, which are most often triggered by infectious illnesses.
A: In classic CAH, high levels of adrenal-derived androgens affect the development of the external genitalia in 46,XX fetuses, beginning in the first trimester. Clitoral enlargement, partially fused labia majora, and a urogenital sinus in place of separate urethral and vaginal openings are commonly found. The uterus, fallopian tubes, and ovaries are formed normally. In approximately 25% of patients with classic CAH, aldosterone production is sufficient to maintain sodium balance in early childhood. In the absence of newborn screening, affected children will present with signs of androgen excess, such as pubic hair and accelerated linear growth velocity, typically before the age of 4 years, and girls may have clitoromegaly or a urogenital sinus that was not noticed earlier in life. The mild hyperandrogenism associated with nonclassic CAH can develop in adolescence or adulthood in affected females but is asymptomatic in postpubertal males. Symptoms may include hirsutism, acne, menstrual dysfunction, subfertility, and recurrent miscarriages, but there may be no symptoms at all. The clinical features are difficult to differentiate from the more common polycystic ovary syndrome, and steroid testing is needed to establish the diagnosis. Short stature in adulthood is a consequence of both hyperandrogenism and glucocorticoid treatment in patients with CAH.
A: Many men with classic CAH have oligospermia or azoospermia for at least two reasons. First, elevated adrenal-derived androgen levels provide negative feedback to the hypothalamic–pituitary–testicular axis, suppress both gonadotropin secretion and testosterone synthesis from Leydig cells, and prevent spermatogenesis. Second, testicular adrenal rest tumors (TARTs) develop in 30 to 50% of adolescent boys and men with classic CAH, particularly after periods of poor control or nonadherence to treatment. TARTs are usually bilateral and arise from the rete testis. The tumors are easily identified with ultrasonography. TARTs can cause irreversible damage to the Sertoli cells and developing germ cells. The presence of a TART and elevated follicle-stimulating hormone levels are poor prognostic factors for male fertility.